NEURONAL SIGNAL TRANSDUCTION: LOCAL REGULATION OF SYNAPTIC STRENGTH AT AN EXCITATORY SYNAPSE
Glutamate released at excitatory synapses can bind to several different classes of receptors including ligand regulated ion channels for sodium (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; AMPAR) and calcium (N-methyl-D-aspartate receptor; NMDAR), as well as several types of G-protein coupled metabotropic glutamate receptors (mGluRs).Repeated firing at such synapses results in modulation of synaptic strength through several mechanisms, including increased levels of the second messenger Ca+2 via NMDAR, which enhances AMPAR action by activation of a calciumcalmodulin kinase II (CaMKII) dependent pathway resulting in AMPAR phosphorylation and increased AMPAR recruitment and stabilization.
Group I mGluR are generally found on postsynaptic sites and can further increase synaptic strength by Gq-mediated activation of phospholipase C gamma 1 (PLCγ1), leading to production of inositol 1,4,5-triphosphate (IP3) and release of calcium from endoplasmic reticulum (ER) stores by activation of the inositol 1,4,5-triphosphate receptor (IP3R). In contrast, groups II and III mGluRs, which are typically present on presynaptic sites, lead to decreased release of glutamate via their G-protein coupled second messengers, resulting in feedback inhibition of the process. Other factors such as brain-derived neurotrophic factor (BDNF) can modulate glutamatergic signaling by activating tropomyosin receptor kinase B (TrkB), resulting in activation of PLCγ1 and IP3-dependent calcium release from the ER.